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News and analysis from the intersection of genomics, personalized medicine and the lawThu, 29 Jan 2015 18:53:40 +0000en-UShourly1http://wordpress.org/?v=4.0.1Conley Q & A on LDTs and the FDAhttp://www.genomicslawreport.com/index.php/2015/01/29/conley-q-a-on-ldts-and-the-fda/
http://www.genomicslawreport.com/index.php/2015/01/29/conley-q-a-on-ldts-and-the-fda/#commentsThu, 29 Jan 2015 18:52:27 +0000http://www.genomicslawreport.com/?p=13394In her recent post on the FDA’s draft guidance on its proposed oversight of Laboratory Developed Tests (LDTs), Jen Wagner mentioned my interview with Genome Web’s Turna Ray on January 15, 2015. Turna asked me to address some arguments made in a “white paper” written by former U.S. Solicitor General Paul Clement and Harvard law professor Laurence Tribe on behalf of their client, the American Clinical Laboratory Association. The main point that Clement and Tribe made was that the FDA lacks legal authority to oversee LDTs, at least in the way that it’s proposing to do so. As I told Turna, I don’t necessarily disagree with their position; in fact, I’m skeptical about the FDA’s authority to do this. Also, like Jen, I’m not persuaded the proposed FDA initiative is likely to work well from a practical perspective. Nonetheless, I agreed to play along in a devil’s advocate exercise, making the counterarguments I’d make if representing the FDA. Here’s a brief summary of my arguments:

This wasn’t actually one of my arguments, but—isn’t “white paper” a little pretentious? The term came out of British government practice, and originally referred to an authoritative statement of the government’s position on some important issue. This is an advocacy piece written by lawyers on behalf of a client. It’s a paper (if you print it out), and it’s white (unless you print it on colored paper), but hardly in a league with the British White Paper of 1922 expressing support for a Jewish homeland in Palestine.

Tribe and Clement argued that the sequence and content of several Congressional enactments, including the Clinical Laboratory Improvement Act of 1967 (CLIA), the Medical Device Amendments of 1976 (MDA), and the CLIA Amendment of 1988, add up to a statement that Congress did not believe that the FDA had jurisdiction over LDTs. Tribe and Clement put particular emphasis on the argument that MDA covers “devices” and “articles,” “words that don’t naturally apply to clinical laboratory testing services.”

I responded that you can’t wring that much Congressional intent out of CLIA and MDA. They were separate pieces of legislation that dealt with discrete problems: CLIA, with the workings of labs; and MDA, with medical devices. I don’t see the juxtaposition of the two laws as evidence of any considered Congressional understanding of LDTs. And by the way, why don’t words like device and article “naturally” apply to lab testing? Doesn’t that process use concrete articles and devices? The definition of devices in MDA is very broad.

Tribe and Clement argued that the use of LDTs is part of the practice of medicine, which has always been understood to be a matter of exclusive state regulation, beyond the purview of the FDA and other federal agencies. The latter point about state jurisdiction is non-controversial. But what does that prove about LDTs? The federal government can’t regulate a radiologist’s exercise of judgment—that’s the practice of medicine. But can’t it regulate x-ray and scanning machines as medical devices?

Tribe and Clement argued that the FDA’s position is undercut by the fact that, all of a sudden, it’s going to assert regulatory authority when “they haven’t exercised this authority for 40 years.” Doesn’t this suggest that the FDA really believed that it never had such authority? An admission by conduct, by analogy to the law of evidence. My response is that regulators and prosecutors do this sort of thing all the time: they ignore a problem for a long time and then (often under public pressure) decide that it’s gotten more serious and that they need to act. I used the example of broken windows policing. I said: “If you apply that kind of logic to the FDA, their position is that they’ve always had this authority to [regulate LDTs], but in terms of priorities for their limited resources, given the nature of the LDT market, they didn’t think it was a good use of those resources. Because LDTs have become a bigger business, they’re more important, FDA now thinks LDTs pose a higher level of risk and they’ve decided to change their view on that.”

Tribe and Clement also objected to the FDA’s use of the “guidance” process rather than formal rulemaking under the Administrative Procedure Act, which is supposed to be the basis for the modern regulatory state. I’m not sure there’s a good counter to that, except that federal agencies—including the FDA—frequently try to avoid formal rulemaking, with its built-in delays and opportunities for judicial review. But that doesn’t make it right, legally or politically. As I said, the best that the FDA can do here is something along the lines of, “We don’t have to go through the full APA rulemaking procedure because we’re not actually issuing a binding rule. All we’re saying is we always had this regulatory authority and we’re just being transparent about when and how we’re going to exercise it.”

]]>http://www.genomicslawreport.com/index.php/2015/01/29/conley-q-a-on-ldts-and-the-fda/feed/0Groundhog Day: FDA and Proposed Oversight of LDTshttp://www.genomicslawreport.com/index.php/2015/01/22/groundhog-day-fda-and-proposed-oversight-of-ldts/
http://www.genomicslawreport.com/index.php/2015/01/22/groundhog-day-fda-and-proposed-oversight-of-ldts/#commentsThu, 22 Jan 2015 16:30:41 +0000http://www.genomicslawreport.com/?p=13382Once again, attention in Washington, DC has turned to the Food and Drug Administration (FDA) and its proposed oversight of all laboratory developed tests (LDTs). The occasion for this attention was the FDA’s separate releases on October 3, 2014 of its proposed LDT framework and proposed notification and medical device reporting guidance. The former describes the basic structure for how the FDA intends to exercise its authority over LDTs as medical devices (e.g., risk classification and enforcement discretion categories), and the latter describes the process by which laboratories offering LDTs must notify the FDA of all LDTs (i.e., registration) and the adverse event reporting requirements that would apply to LDTs as medical devices (i.e., reporting of deaths, serious injuries, malfunctions, etc.). The agency hosted a public meeting on January 8-9, 2015 to discuss the proposed guidance and is accepting written public comments until February 2, 2015. [No joke: Comments are, in fact, due on Groundhog Day.]

The public meeting featuring speakers and panelists was organized into six topical sessions covering test components and labeling; clinical validity and intended use; categories for continued enforcement discretion; notification and adverse event reporting; classification and prioritization; and quality system regulation. The FDA has promised to post the transcript (and, in the meantime, some live tweets from the meeting will remain available on @DNAlawyer’s feed). Dr. Jeff Shuren started the meeting with a reminder that the FDA’s proposed guidance was based on discussions held five years ago, in 2010. (Prior GLR coverage is here.)

Most speakers and panelists avoided challenging or defending the FDA’s legal authority to regulate LDTs altogether and, instead, engaged in productive dialogue focused on deficiencies, ambiguities, and anticipated consequences of the proposed guidance. The legal heavy-hitters representing the American Clinical Laboratory Association (ACLA), Paul D. Clement and Lawrence H. Tribe, published a White Paper on January 6, 2015 detailing the argument against the FDA’s claimed authority to regulate all LDTs. GLR’s own John Conley provided a devil’s advocate counter-argument to Clement and Tribe in a recent Q&A for Genome Web. Participants in the FDA’s public meeting generally acknowledged that the important question of authority must be resolved. Many speakers suggested opposition to or support for FDA authority while indicating that they would focus their limited allotted time on other topics, and some even expressed outrage (notably including Edward Ashwood (ARUP) who was applauded following remarks that he was “absolutely outraged” by the FDA). One panelist, Bradley Merrill Thompson, attempted to lead the meeting’s attendees in a useful mental exercise to help identify the crux of the challenges involved with FDA oversight of LDTs. Thompson used hypothetical scenarios to ask a series of questions designed to identify underlying factors relevant to identifying the legal line between the provision of professional medical services and the the manufacturing of pharmaceuticals—in other words, when does the LDT become an in vitro diagnostic (IVD) that is unquestionably subject to oversight by the FDA? Unfortunately, the exercise was disrupted by a disgruntled audience member and left unfinished as the session moderator had the panel move forward. Thompson subsequently published his exercise and accompanying thoughts online; he noted that both sides in the authority debate may be overlooking limitations in their arguments and concluded that some LDTs are outside the scope of the FDA’s reach and the legal distinction is not as simple as identifying the actor (i.e., laboratorians versus manufacturers).

The gist of the discussions from the public meeting can be conveyed with a number of clichés (e.g., Tilting at Windmills, Lost in Translation, Devil is in the Details, Long Row to Hoe, etc.). And it definitely feels as if we have had this conversation and heard many of the frustrations expressed before. Nevertheless, the public meeting’s discussions can be distilled into a few points. First, the FDA’s draft guidance struggles with fundamental definitions that must be resolved. These definitional problems are not semantic quibbles but, rather, fundamental issues with big impacts regarding who needs to comply with what requirements and when. Second, the anticipated costs and benefits of the proposed oversight appear to have not yet been adequately weighed. For example, at the end of the day, will this framework be a net gain and improve safety and efficacy of LDTs? Some participants suggested current industry practices and existing oversight already ensure validity of results and that the real dangers of LDTs are their misapplication and misinterpretation. Both of the latter are beyond the reach of the FDA and thus would remain unchanged even if the proposed guidance were implemented. Are the added administrative burdens justifiable? Third, details regarding the risk-classification system and use of expert panels should be provided sooner rather than later. A frequent remark was that the draft guidance is an outline and more details need to be provided so that stakeholders can consider the FDA’s plans as a whole before compliance can be expected.

Here are some more detailed thoughts on each of these three points:

You say tomato, I say tomahto. Ok, but is it a fruit or a vegetable? It depends on the context. And what about Ketchup by extension?
Scientific facts are not always synonymous with public perceptions or legal facts and distinctions. Terms can make all the difference in how the problem is conceptualized, how the draft guidance is finalized and operationalized, and how the guidance is understood. A number of troublesome areas have been highlighted and require us to consider not only what question is being asked but also why we are asking the question and who gets to decide the answer. Meeting participants expressed angst, confusion, and concern about a number of terms, including test, intended use, clinical validity, rare disease, and health care system. For example, is an LDT performed in multiple sites the same test? Does each minor modification done routinely in industry practice trigger obligations to submit as a “new test”? Intended use might not be the same as indicated use, and new FDA terminology for laboratories may be a source of confusion. Clinical validity encompasses much more than just performance characteristics. Defining rare disease for purposes of LDT oversight discretion illustrates just how difficult it is for the FDA to function in the era of next generation sequencing. Multiple participants challenged the threshold of fewer than 4000 individuals tested per year and compared the threshold for orphan drug classification of a disease affecting fewer than 200,000 patients nationwide. Moreover, numerous concepts of health care system were mentioned (such as facilities under the same CLIA number, facilities within the same accountable care organizations, facilities within a payer or insurance provider’s network, etc.), each with different challenges for implementation and different consequences for individual access and patient care. Some of the confusion from the terms and language in the draft guidance is, as Catherine Hammett-Stabler (American Association for Clinical Chemistry) and others noted, attributable to “‘FDA speak’ versus ‘lab speak.’”

Costs and Benefits Analysis Needed
How will the FDA handle the flood of submissions? Delays are inevitable, but how will those delays affect health care and public health responses? Will the administrative burden of this proposed undertaking unnecessarily divert scarce FDA resources from other areas that should take priority? Nick Harris (IGeneX) questioned why the FDA would even think of adding to its existing bottleneck. Ultimately, will patients and consumers see improved quality of LDTs and improved care? Curtis Hanson (Mayo Clinic) spoke about the need to understand what problem we’re trying to fix here. After citing that Mayo has had over 21 million LDTs and zero sentinel events, Hanson directly asked, “What’s the problem?”

The proposed guidance describes an FDA LDT framework that will create a very large workload, a topic mentioned by many, including James Prescott (PathGroup). Some speakers, such as Paul Kim (Foley Hoag), suggested that the FDA could overcome some of the administrative challenges by exploring outside expertise and resources. A number of participants commented that the new oversight framework is all but guaranteed to stifle innovation and development, increase costs, and limit LDT options. Infectious disease and public health stakeholders weighed in, emphasizing the need for flexibility. For example, Amanda Jezek (Infectious Disease Society of America) warned that many clinical microbiology labs might stop using LDTs entirely as a result of the FDA’s proposed framework. Similarly Stephanie Pang (National Coalition of STD Directors) detailed how sexually transmitted disease screening could be hampered by the proposed guidance. The implementation of the proposed guidance, in the context of existing routine payer practices, could have serious unintended effects as well and may not have been adequately anticipated. For example, if a lab obtains novel FDA approval for an LDT for a particular condition, that FDA approval will disrupt access and likely increase the cost of health care for many individuals for whom the lab is considered by payers to be “out of network.”

When weighing costs and benefits, it would be useful to compare the proposed FDA framework with an enhanced CLIA framework and to consider savings that could be generated through harmonization efforts and unified regulatory submission systems (e.g., in which one submission would elicit information about the LDT at sufficient levels of granularity for multiple purposes). Andrew Hoofnagle (University of Washington) explained at the meeting that a side-by-side comparison of current CLIA requirements for laboratories and proposed FDA requirements for LDT manufacturers has been created, but that comparison has not yet been shared with the public. Such transparency would assist all stakeholders in understanding what the proposed guidance is intended to do and would enrich the quality of feedback that could be provided to the FDA prior to finalization.

Details on Risk Classification and Expert Panels Remain Fuzzy
As Paul Radensky (Coalition for 21st Century Medicine) pointed out at the meeting, risk classification on a case-by-case basis cannot start until a baseline of details are known. For example, what factors are to be considered? What duties follow the particular risk classification? Paul Kim (Foley Hoag) stated that broad classifications for LDTs will simply not be possible, and—given the continuous innovation of LDTs—companies themselves might possess the best expertise for assessing and classifying risk. Amy Miller (Personalized Medicine Coalition) similarly noted that current conflicts of interest rules create challenges for the expert panels and that creativity is needed to ensure that individuals with the right expertise are able to answer the necessary questions. Miller underscored the importance of a robust public examination of the FDA’s plans and emphasized that diverse stakeholders must continue to be engaged in the policymaking process. Leonard Lichtenfeld (American Cancer Society) highlighted that the expert panels need to verify that claims about LDTs are supported but, to do so, those expert panels must understand what evidence would be reasonable. From the discussions, it seemed that many believe that multiple expert panels are necessary and further believe that each expert panel must be discipline-specific. The expert panels are charged with classifying LDTs and then making case-by-case determinations on LDT submissions. Given all this, the proposed framework invites questions as to whether it is needed at all. For example, how is this an improvement over the current CLIA oversight and self-governance of the industry through existing mechanisms of quality control (e.g., reliance upon literature that passes rigorous peer review; laboratory reputations that spread quickly; flexible standards of care in the medical profession to accommodate modifications and advances in testing; emerging standards and databases that improve transparency; etc.)?

Looking Ahead
In light of the discussions at this public meeting, most would agree that finalizing the guidance on the LDT framework and notification and medical device reporting this year is a highly unlikely outcome. Given the ambiguities in basic terminology, lack of details, and scope of the regulatory burdens the proposed oversight would usher in, another round (or two) of draft guidance and discussion is warranted. For better or worse, the FDA seems interested in wrapping this up quickly and has put final guidance on both matters on its “A-List” of policy priorities for FY2015.

On September 5, the Federal Court of Australia (the appeals court) upheld a claim on isolated DNA from the BRCA1 gene. It dismissed Yvonne D’Arcy’s appeal of a case that has attracted international attention. Australian patent 686,004 has never been enforced, so the court decision has little real-world concrete impact. As Richard Gold and Julia Carbone explained in their classic case study, “Myriad Genetics: In the Eye of the Policy Storm,” the patent rights on BRCA1 and BRCA2 were exclusively licensed for use in Australia and New Zealand to Genetic Technologies, Ltd. (GTG), which in turn made them a “gift to the people of Australia.” When the CEO of GTG proposed taking back that gift in the summer of 2008, he provoked a firestorm and the company backed down in October, restating that it would not enforce its patent rights against laboratories offering BRCA testing. The Australian Senate held a series of hearings, and a bill proscribing DNA sequence patents was proposed, but the new government opposed it, and it lapsed. Instead, Australia enacted patent reforms in 2012 that raised the bar for utility and clarified the Australian law’s exemption from infringement liability for research and regulatory approval. Most of the provisions of that law took effect on April 15, 2013, the very day Association for Molecular Pathology v Myriad Genetics (AMP v Myriad) was argued before the U.S. Supreme Court.

It is ironic that in the United States, the only jurisdiction in which BRCA patents have been enforced, the courts invalidated Myriad’s claims to DNA molecules whose sequence is found in nature as well as most of its method claims (except one method claim on use of BRCA as a chemotherapeutic assay in drug discovery, not relevant to diagnostic testing). In Australia, where BRCA patents have never been enforced, claims on isolated DNA molecules have now been upheld at the appellate level, affirming Judge Nicholas’s trial court decision of February 2013.

In the United States, Myriad began to sue competitors that offered BRCA testing in July 2013, less than a month after the Supreme Court decision of June 13. These suits are based on claims not challenged in the case that went to the Supreme Court (with the exception of one claim on 15-base pair segments of BRCA1 DNA that was challenged but whose validity is unclear under the Supreme Court ruling). Myriad has sued eight competitors. One such competitor (Gene by Gene) settled in February 2014. Pre-trial proceedings for the other cases have been consolidated in the Utah federal District Court and assigned to Judge Robert Shelby. The competitor companies currently in litigation are Ambry Genetics, Counsyl, GeneDx, Invitae, LabCorp, Pathway Genomics, and Quest Laboratories. Several of the firms have petitioned for declaratory judgment of non-infringement, and one (GeneDx) has challenged eleven of Myriad’s patents through a request for Inter Partes re-examination by the U.S. Patent and Trademark Office. Judge Shelby denied Myriad’s request for a preliminary injunction, which means that the competitors can continue to offer testing, although they will be liable for damages if they are found to infringe valid patent claims. They could also be subject to a permanent injunction at the conclusion of the case.

The Australian appeals court’s ruling was a unanimous decision of the five-judge panel, which included the chief judge. Australian court decisions are not “signed” by particular judges, unlike U.S. practice, but Judge Annabelle Bennett is widely regarded as the source of the key arguments, based in part on her background in biotech patent law and her Ph.D. in biochemistry from the University of Sydney. She formerly advised the Australian Law Reform Commission in its report on gene patenting.

The Australian ruling runs to fifty pages. Ten of those pages are a primer on DNA biochemistry. The core of the legal reasoning, however, clearly states that a distinction between invention and discovery is not a fruitful conceptual framework for patent law, and quite explicitly rejects the U.S. Supreme Court’s arguments in AMP v Myriad. The opinion lauds Judge Lourie of the U.S. Court of Appeals for the Federal Circuit, who upheld Myriad’s claims on isolated DNA molecules in two majority opinions that were unanimously reversed by the U.S. Supreme Court.

There are several reasons for the difference between the Australian and U.S. court decisions. One is Australian legal precedent. Australia’s 1990 patent statute rests squarely on Section 6 of the 1624 English Statute of Monopolies. Under Australian law, patents are available for an invention that:

(a) is a manner of manufacture within the meaning of section 6 of the Statute of Monopolies; and (b) when compared with the prior art base as it existed before the priority date of that claim:

(i) is novel; and (ii) involves an inventive step; and

(c) is useful…

The key Australian case for interpreting “manner of manufacture within the meaning of Section 6” is a 1959 case called National Research Development Corporation v Commissioner of Patents that requires that an invention apply to an “artificially created state of affairs.” The High Court (Australia’s equivalent of the Supreme Court) held in that case that “the distinction between discovery and invention is not precise enough to be other than misleading” and set a low bar for patent eligibility. This criterion in effect means that if “we did it in our lab” it will clear the threshold for patent eligibility. Given this precedent, the Federal Court’s ruling is sensible. This did not stop the court from expanding into dicta, and going out of its way to chide and take issue with the U.S. Supreme Court for its line of reasoning.

The Australian Federal Court dismissed the concern for blocking access to genetic information by asserting that the patent claims molecules, not information. The court reasonably noted that the information about BRCA sequences is now known and can be used without infringement. The published sequences can be copied and used freely. It failed to acknowledge, however, that by granting exclusive rights to isolated DNA molecules it thereby blocked determination of the DNA sequence of—and thus the information stored in—any as yet-unsequenced DNA molecule. No DNA will ever be sequenced without being isolated. Isolation is by definition an attribute of a DNA molecule whose sequence is being determined. Such sequencing entails the hand of man, but the sequence also comprises information that was and always will be “found” from a sample to be analyzed, not invented by the team that first discovered the gene. DNA is the storage and transmission medium of genetic information, and by granting patent rights to isolated DNA molecules, the decision means that any study or analysis of a natural gene by a human being will infringe such patent claims. The Federal Court of Australia was content to note that the information itself is not patented, but this is not the killer argument that the Court presumes. Those who view DNA as a unique informational molecule will not be persuaded that the Australian court has fully appreciated the consequences of its focus on DNA as a chemical without acknowledging its informational role. Indeed, the Australian court seems not to have dismissed the U.S. Supreme Court’s concern, but rather to have entirely missed it.

The Myriad/Utah team cloned and sequenced the BRCA1 gene and identified several cancer-associated mutations in it. This was hard work and they won a hard-fought global race to find a gene known to be residing on chromosome 17, set off by Mary-Claire King’s landmark 1990 publication establishing linkage to a cancer susceptibility locus she named BRCA1. In discovering the gene, they also invented (or discovered—here there is little need for a distinction) a way to detect sequence variations for purposes of research or diagnosis. By the logic of patent law, they were entitled to a patent right. Moreover, as the Federal Court of Australia explicitly pointed out, they also provided sufficient information (if one grants the right to correct the many sequence errors in their initial sequence) to produce the BRCA1 protein. One does not need more than the sequence specified in the patent application to do that, and if the BRCA protein had been an effective treatment, this could have been a potentially lucrative patent analogous to patents on genes for making insulin, growth hormone, erythropoietin or other therapeutic proteins.

In finding the gene, the Myriad/Utah team found a way to detect sequence variations, and that is an invention. But they claimed far more than they invented by claiming the DNA molecules—both the ones they actually characterized and those yet to be discovered. This includes either DNA extracted from samples or made into copies. The Australian court and most commentators have focused on how the patent right should extend to DNA molecules themselves—and in some contexts that is undoubtedly true. But by allowing claims on isolated DNA molecules, the court thereby caused a serious problem of pre-emption of future research, because of the informational role of DNA.

Many molecules have been patented that are found in nature: adrenaline, antibiotics, vitamins, hormones and growth factors, vaccines, and other products. In those cases, the molecules are put back into bodies to change them, and it is natural to conclude those result from human intervention and “invention” in a meaningful sense. When doing a diagnosis or conducting an experiment, however, the “isolated” DNA molecule being sequenced is not useful in itself, but is only an informational intermediary. It is useful if and only if the “isolated” DNA exactly copies the information content of the sample DNA. If the “isolated” DNA differs from the sample in its information content, it is useless as a diagnostic test or scientific method; it is a sequencing error. The sample DNA, however, is not invented by anyone; it is found in nature. According to the U.S. Supreme Court, it should not be claimed in a patent.

Here the distinction between discovery and invention does hard work. The DNA sequence of the sample to be analyzed cannot be known in advance, and the sequence itself is not the result of human work; for purposes of diagnosis, the DNA molecule is simply the embodiment of the sequence information, and the purpose of the test is to capture the information via the DNA sequence, not to obtain the DNA molecule itself. The crucial input for diagnosis or scientific inquiry is sample DNA but the crucial output is information. There is thus a two-pronged test to distinguish claiming an isolated DNA molecule to direct production of a protein, which is patentable, from claiming the molecule when the output is information, where the U.S. and Australian courts disagree about whether it is patentable. Does the DNA molecule’s claimed sequence reside in nature and is it, by definition, not known in advance? The very purpose of a genetic test is to extract information residing in the sample DNA and to resolve uncertainty about whether it harbors a deleterious mutation. That is, the input is sample DNA of unknown sequence and the output is information; the DNA molecule is merely an intermediary. The second distinction is that the information is the only product; whereas for gene patents on DNA encoding therapeutic proteins (or for patent claims on antibiotics, vitamins, vaccines, hormones, growth factors and other patented biological molecules found in nature), the end product is a molecule that will be put into someone’s body in order to change its biology.

The Federal Court of Australia is persuasive that Myriad invented something useful, but unpersuasive that its claims should be as broad and should extend to naturally occurring sequences. By granting the rights claimed, the Federal Court of Australia has in effect blocked any way of getting access to that information by what truly does seem to be a “lawyer’s trick,” the use of the magical word “isolated.” The court has extended an exclusive right to the study of DNA; any means of determining the sequence of a DNA molecule containing one of the claimed mutations from a person’s cells will infringe the claim during the term of the patent. The Myriad/Utah team discovered the gene, and thereby invented something that is new, useful, inventive, and commercially valuable. But they did not invent everything that they claim. This is not a case of rewarding or failing to reward the act of invention, but of precision in claiming what has actually been invented—and what has not.

Sometimes discovery and invention are close synonyms, and sometimes they are not. By rejecting any distinction between invention and discovery across the board, the court has bred more confusion than it avoided. It has failed to acknowledge a situation in which the distinction between invention and discovery can do hard legal work. The Myriad/Utah team did indeed do something valuable and inventive, but they did not invent the molecules claimed as:

An isolated nucleic acid coding for a mutant or polymorphic BRCA1 polypeptide, said nucleic acid containing in comparison to the BRCA1 polypeptide encoding sequence set forth in SEQ.ID No:1 one or more mutations or polymorphisms selected from the mutations set forth in Tables 12, 12A and 14 and the polymorphisms set forth in Tables 18 and 19.

They characterized those molecules by making laboratory copies, but they did not invent them. The DNA molecules so described encode a mutant BRCA1 protein. And the Myriad/Utah team thus did indeed invent a way to make the gene in a laboratory and turn it into protein, and they can claim that invention as a process. Or they can claim specified DNA molecules that do not reach to all ways of determining DNA sequence. But it is not clear they should be able to claim DNA molecules they discovered and did not invent. Yet the scope of the claim encompasses such molecules in addition to those they actually did make and describe in their patent. The Australian court has said yes, they can claim them; the U.S. Supreme Court has said the opposite.

In its zeal to protect patents on the DNA that can produce the BRCA1 protein, the Australian court passed over in silence how DNA molecules are used for diagnosis and when doing research. When doing a diagnosis of a sample sent for analysis or when doing research, the molecules created in the laboratory’s “artificial state of affairs” come not from Myriad but depend entirely on the sample DNA being analyzed. That DNA was not invented by the Myriad/Utah scientists. Both Judge Nicholas and the Federal Court of Australia argued that the DNA molecules that Myriad made in the lab when discovering BRCA1 are different from those in the body. By the same logic, then, the “isolated” molecules Myriad claims are also necessarily different from the natural DNA in cells and bodies that are the subject of diagnostic testing or research. The molecules are by definition being created de novo for each test or experiment, based on a natural template. Should they fall under the scope of Myriad’s claims? Whether the discoverers of the gene should be able to claim the molecules copied from the natural source is not an obvious or easy decision. It is certainly not the slam dunk argument the Federal Court of Australia took it to be.

Infringing uses of the claim as granted include diagnosis and also research. In Australia, some research will infringe, but be exempt from infringement liability because of the research exemption that was clarified in Australia’s 2012 statute. The U.S. has no such brake on patent rights, however. Since the Federal Circuit’s decision in Madey v Duke University (2002), the absence of a meaningful research exemption in U.S. law has been apparent. Any research that has practical uses, even nonprofit research at academic institutions, infringes patent claims. Only research that is purely for satisfying curiosity has a chance of escaping infringement liability in the United States.

The U.S. Supreme Court was therefore quite right to be worried that exclusive rights can be enforced against research. The vast majority of the thousands of papers published on BRCA1 and BRCA2 infringe the kind of patent claims upheld by the Australian court. Myriad initiated a suit against the University of Pennsylvania when it was going to be a BRCA testing hub for National Cancer Institute grants that would involve BRCA testing in research, so there is precedent for being concerned about infringement liability in research. While the Australian Federal Court gave short shrift to pre-empting research, it was a major concern of the U.S. Supreme Court. Myriad’s pledge not to enforce patents against noncommercial research—a pledge made just as it filed suits against competitor commercial testing laboratories in July 2013—will give cold comfort, since enforcement is entirely at the discretion of the patent-holder, not a matter of law.

The next step of appeal, to the Australian High Court, is subject to the discretion of that Court. The case that was heard by the U.S. Supreme Court came with a very different history. U.S. BRCA patents had been entirely invalidated by Judge Robert Sweet at the district court level, and the Federal Circuit had reversed him in a 2-1 split decision with a dissenting opinion. Moreover, the U.S. Solicitor General weighed in, and urged both the Court of Appeals and the Supreme Court to uphold patents on engineered DNA, but to consider DNA molecules corresponding to sequences that can be found in nature to be unpatentable subject matter. The U.S. Supreme Court thus faced a CAFC reversal of a district court decision, a split within the CAFC, and a Solicitor General amicus brief that tracked the CAFC dissent, not the majority. The U.S. Supreme Court’s intervention thus addressed mixed verdicts in lower courts and disagreement within the executive branch (between the Department of Justice, as represented by the Solicitor General, and the Patent Office, which had allowed the patent in the first place). In Australia, in contrast, both the trial court and the appeals court have upheld patents on isolated DNA molecules, so there is less legal uncertainty for the High Court to resolve. And there is little real-world impact because the patents have never been enforced, will soon expire, and the Australian licensee has just sold its rights to molecular diagnostic testing in Australia.

That said, the High Court could revisit its 1959 summary rejection of a distinction between invention and discovery. As Chris Dent notes in his history of the 1624 Statute of Monopolies, the law is anything but precise. It was a result of compromise and probably also deliberate ambiguity. The lexical precision (some would say pseudo-precision) of the Federal Court of Australia’s ruling confronts a long history of balancing and ambiguity in patent law. The Australian precedent relies on a 55-year old case that gave an expansive definition of patent-eligibility and obliterated the invention-discovery distinction. Many patent lawyers and scholars have since argued that the invention-discovery distinction is outdated and introduces needless uncertainty into the legal determinations of patent-eligibility. Many argue that novelty, utility, non-obviousness (or inventive step), enablement, and adequate written description can do the work of weeding out bad patent claims with greater clarity and precision than standards for deciding what kinds of things can be patented at all—the doctrine of patentable subject matter. The 1952 U.S. patent statute and dicta in the landmark Diamond v Chakrabarty case of 1980 both affirmed that patents could be sought on “everything under the Sun that is made by man,” with the emphasis on “anything” more than on “made by man” (ignoring both the archaic sexism and the clear invocation of invention versus discovery). The U.S. Supreme Court has repeatedly rejected this expansive interpretation of the U.S. Patent Act, most recently in at least one case per year for the past four years (Bilski, Mayo, Myriad, and Alice). The Australian courts to date have not walked back, and so distinguishing invention from discovery is not the basis of case law there. There are, however, several “escape clauses” in the 1624 Act that have been little exercised in modern jurisprudence, including a rejection of patents when they are “generally inconvenient.” The invention-discovery distinction could still lie dormant and the High Court could bring it back to life should it choose to do so.

The High Court of Australia may or may not accept the promised appeal. If it does not, then U.S. and Australian law will have quite different jurisprudence for DNA-sequence-based patents for the foreseeable future. The politics and consequences of this discrepancy between patent jurisdictions are only partially predictable.

The drumbeat for lobbying the U.S. Congress to “fix” the results from the Supreme Court’s decisions in both Myriad and Mayo v. Prometheus (2012) is getting louder. Some are arguing that the international Trade-Related Aspects of Intellectual Property agreement (TRIPs) might compel the United States to adopt laws that interpret patent criteria in the same way that the Federal Court of Australian and the European Biotechnology Directive of 1998 do, explicitly permitting patents on DNA molecules whose sequences correspond to those found in nature.

Those contemplating a statutory fix might, however, be chastened by the changing politics of intellectual property. It was mainly patent lawyers and industry leaders who tweaked statutory definitions in the Biotechnology Process Patent Protection Act of 1995. A few years later, in 1999-2001, the Patent Office tweaked its examination guidelines for utility and written description in a process that CAFC Judge Bryson characterized as “cursory” in his Myriad dissent. Those changes did not elicit strong responses from cancer advocacy organizations, the American Civil Liberties Union, or high-tech open-source advocates. Today, disease advocacy groups, cancer patients, scientists, civil libertarians, and high-tech open-source advocates are potent and engaged. They will surely oppose backroom deals to expand gene patent rights; it will not be an inside game. The politics of patent law are getting more complicated, noisier, more contentious, and involve broader constituencies than the patent bar is accustomed to encountering.

In Australia, rights on gene patents have not been enforced against diagnostic or research use, and yet the courts have upheld patents on isolated DNA molecules whose sequences would be found in nature; in the United States, rights have been enforced, but patent rights have been weakened and constituencies will be fully engaged and attentive if efforts are made to restore them. Battles in Congress will not be quiet or quick, so picking battles may require discretion. The big winners in this cauldron of confusion are patent scholars who have plenty to write about. And patent lawyers who can make hay 24 hours a day, because the sun is always shining on a jurisdiction with uncertain patent rights.

Robert Cook-Deegan, MD, is Research Professor at the Sanford School of Public Policy, Duke University, with appointments also in Medicine and Biology.

]]>http://www.genomicslawreport.com/index.php/2014/09/30/australian-appeals-court-upholds-patents-on-isolated-brca1-dna/feed/0Medical Organizations Can’t Shape the Rules for Admitting Expert Testimonyhttp://www.genomicslawreport.com/index.php/2014/08/19/medical-organizations-cant-shape-the-rules-for-admitting-expert-testimony/
http://www.genomicslawreport.com/index.php/2014/08/19/medical-organizations-cant-shape-the-rules-for-admitting-expert-testimony/#commentsTue, 19 Aug 2014 13:00:34 +0000http://www.genomicslawreport.com/?p=13353A little more than a year ago I wrote a post about the then-new Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing from the American College of Medical Genetics and Genomics (ACMG). Those Recommendations (since modified somewhat) proposed that whenever a patient undergoes whole-genome or whole-exome sequencing (WES) for any purpose, the laboratory doing the testing should always sequence and report to the ordering physician the results for 57 (now 56) genes on the ACMG’s list. Among the questions I addressed in that post was this one: “Do those Recommendations become by definition the standard of care for the specialty, immediately or in the near future?” I wondered specifically about a future case in which a doctor ordered WES, the lab analyzed only the genes the doctor was interested in, leaving out some of the ACMG’s 56, and the patient subsequently suffered a bad medical outcome linked to an omitted gene. Would failure to follow the ACMG Recommendation be evidence—maybe even conclusive evidence—of malpractice?

A July 29, 2014 decision by the U.S. Court of Appeals for the Eleventh Circuit (which covers Georgia, Florida, and Alabama), Adams v. Laboratory Corporation of America, may shed some light on the question, at least indirectly. That case held that a court should not defer to medical organizations’ standards for what constitutes competent evidence of professional negligence.

Christina Adams had five pap smears during 2006-08. Her doctor sent them to LabCorp for analysis, and was told that there were no abnormal cells. LabCorp’s protocol was for test slides to be examined under a microscope by a trained technician called a cytotechnologist, who would send the slides to a pathologist only if abnormal cells were detected. Ms. Adams experienced vaginal bleeding in 2009 and was then diagnosed with advanced cervical cancer. She and her husband sued LabCorp for negligence, alleging that the cytotechnologists who reviewed her slides breached the standard of care that applies to the practice of cytotechnology.

To prove the breach, the Adamses planned to rely on the testimony of Dr. Dorothy Rosenthal, a professor of pathology at Johns Hopkins with 40 years of experience. The federal district (trial) court in Georgia, having reviewed Dr. Rosenthal’s pre-trial deposition, ruled that her testimony would not be admissible at trial. With her testimony excluded, the Adamses had no expert opinion to support their allegations of negligence, so the district court granted LabCorp’s motion for summary judgment (that is, it dismissed the Adamses’ case before trial on the basis that they could no longer possibly win). The Eleventh Circuit reversed, ruling that Dr. Rosenthal’s testimony is admissible, vacating (undoing) the grant of summary judgment, and remanding (sending back) the case to the district for further proceedings, which will presumably include a trial. All three judges on the Eleventh Circuit panel concurred in the judgment, with one of the three writing a separate opinion.

The general requirements for expert testimony in the federal courts are set out in Federal Rule of Evidence 702, which is in turn derived from three Supreme Court cases decided in the 1990s—the so-called Daubert trilogy, named after the first of the three, Daubert v. Merrell Dow Pharmaceuticals. As summarized by the Eleventh Circuit, Rule 702 and the Daubert trilogy require three things: the expert must be qualified to testify competently about the matter at hand, the expert’s methodology must be reliable, and the testimony must be helpful to the jury. The district court rejected Dr. Rosenthal on the basis that her methodology was unreliable in the extreme: “an ipse dixit assessment that is devoid of any methodology that would allow another expert to challenge it in any objective sense.”

So what did Dr. Rosenthal do that was so unreliable? She went to LabCorp’s Atlanta facility and examined all of Ms. Adams’ slides under the same model microscope that the LabCorp cytotechs had used. She then applied the long-standard Bethesda System (which she had helped to develop, and which LabCorp also used) to classify the cells, and pointed to abnormal cells that, in her opinion, should have been identified by LabCorp. As the district court emphasized, she knew in advance that the patient had cervical cancer, she didn’t mix Ms. Adams’ slides with those of other patients (in other words, she didn’t do a “blinded review”), and she testified in her deposition that she had a “philosophical bent” in favor of patients who are later diagnosed with cancer.

The district court gave four grounds for its decision, and the Eleventh Circuit found all four to be “manifestly erroneous.” I want to focus on just one, so I’ll discuss the other three very briefly. First, the Eleventh Circuit held, Dr. Rosenthal’s opinion was not a mere ipse dixit (she said it). On the contrary, she “formed her opinion by using reliable tools, applying an established body of medical knowledge, and drawing on her extensive experience in the field.” In fact, the court emphasized, LabCorp’s own expert used exactly the same non-blinded approach in developing her opinion that the LabCorp cytotechs were not negligent.

Second, the Eleventh Circuit rejected the district court’s reliance on Dr. Rosenthal’s admitted pro-patient “philosophical bent.” Any such bias—which could be probed during cross-examination—would be a factor for the jury to consider in judging her credibility, but could not provide a basis for a court to exclude her testimony entirely. And third, it was not necessary for Dr. Rosenthal to have conducted her evaluation of the slides under “similar conditions and surrounding circumstances” as those under which the LabCorp cytotechs worked. That, the court of appeals held, is simply not required by the law. In fact it couldn’t be, because such a rule “would bar all expert medical testimony unless the expert has somehow recreated the same conditions that the defendant was under.”

The Eleventh Circuit devoted most of its attention to a fourth issue: the district court’s criticism of Dr. Rosenthal for failing to follow “litigation guidelines” promulgated by the College of American Pathologists (CAP) and the American Society of Cytopathology (ASC). Under those guidelines, pathologists offering evidence in court should use only “blind review” in which “the plaintiff’s slides are mixed in with other normal and abnormal slides,” with the process repeated by multiple reviewers. Dr. Rosenthal didn’t do that, looking only at the plaintiff’s slides in isolation.

The Eleventh Circuit rejected the district court’s reliance on the CAP/ASC guidelines as the “generally accepted standards in the area of pathology or cytotechnology.” On the contrary, it characterized the guidelines as “policy proposals to limit how courts can find the members of the organizations liable for professional negligence when they are sued.” The organizations have thus “moved away from disinterested scientific inquiry and into litigation policy to serve their members own interests.” The law does “not permit delegating to industry groups the gatekeeping duties of the courts.” If such industry efforts succeeded, “why couldn’t pharmaceutical companies adopt guidelines setting high standards of proof for establishing that a plaintiff’s injury was caused by a given drug and justify doing so based on their experience with the complex nature of pharmacology?” It is clear that the court viewed the CAP and ASC as self-interested trade associations protecting their members’ economic interests, and gave no deference to their status as independent professional organizations.

What does this tell us about the potential role of the ACMG Recommendations in future litigation? The AMCG Recommendations and the CAP/ASC guidelines share one significant feature: they are both recommendations for professional conduct promulgated by learned medical societies. But there are also some critical differences. The ACMG Recommendations are intended to guide the conduct of clinicians and laboratories in the day-to-day practice of medicine. They reflect no apparent intent to influence litigation. To the extent they were to come into play in litigation, they would be neutral in the sense of potentially useful to either party. A plaintiff might charge a defendant physician with negligence for failing to test for one the 56 genes. But a defendant physician might also defend a claim by showing that he or she did follow the Recommendations.

The CAP/ASC guidelines, in stark contrast, are written explicitly to shape litigation, to tell courts what methods plaintiffs’ experts must use. In the Eleventh Circuit’s view, they are transparently pro-defendant, a self-serving effort to create a very high methodological bar for plaintiffs’ experts. A plaintiff’s expert might sometimes benefit from the guidelines by showing that he or she met the standard, but the more frequent outcome is likely to be what happened in Adams, with a defendant attacking a plaintiff’s expert for failing to follow the CAP/ASC prescription.

Adams can reasonably be read as supporting several propositions. First, prior cases have held that a medical organization’s practice standards can be relevant in determining the standard of care, and Adams doesn’t undermine that basic principle. However, practice standards are not binding on the courts; at most, they are evidence of what the standard of care should be. Next, courts are likely to follow the lead of Adams and ask whether the standard is a neutral, scientifically-based effort to improve the quality of daily practice (as the ACMG standards clearly are, regardless of whether you agree with them), or an effort to protect the organization’s members from litigation. In the latter case, the result is likely to be just what happened in Adams: rejection, accompanied by scathing rhetoric about a trade association’s attempt to usurp the authority of the courts. In other words, the effort will backfire.

]]>http://www.genomicslawreport.com/index.php/2014/08/19/medical-organizations-cant-shape-the-rules-for-admitting-expert-testimony/feed/0New Article on Myriad Litigation and the Company’s Evolving Strategyhttp://www.genomicslawreport.com/index.php/2014/08/04/new-article-on-myriad-litigation-and-the-companys-evolving-strategy/
http://www.genomicslawreport.com/index.php/2014/08/04/new-article-on-myriad-litigation-and-the-companys-evolving-strategy/#commentsMon, 04 Aug 2014 13:00:52 +0000http://www.genomicslawreport.com/?p=13346GLR editor John Conley has just co-authored a new article in the North Carolina Journal of law & Technology about Myriad Genetics’ response to last summer’s Supreme Court case that invalidated its broadest gene patents. The article focuses on Myriad’s business decision to rely less on patents and more on its vast proprietary database, especially in its growing European operations. The co-authors are Robert Cook-Deegan, M.D., a research professor of public policy and medicine at Duke, and Gabriel Lazaro-Munoz, J.D., Ph.D., a post-doctoral fellow at UNC’s Center for Genomics and Society (where John is also an investigator). The article was included in NC JOLT’s 2014 Symposium, “Gene Patents After Myriad.” The Symposium also includes articles by Sandra Park of the ACLU, who was involved in the Supreme Court case, and law professors Lori Andrews and Christopher Holman. The Symposium can be accessed at http://ncjolt.org/. Here are links to the full Conley, Cook-Deegan and Lazaro-Munoz article the abstract (NC JOLT is Open Access):http://ncjolt.org/myriad-after-myriad-the-proprietary-data-dilemma/

Myriad After Myriad: The Proprietary Data Dilemma

John M. Conley, Robert Cook-Deegan & Gabriel Lázaro-Muñoz

Volume 15, Issue 4 (Jun 2014)
Myriad Genetics’ long-time monopoly on BRCA gene testing was significantly narrowed by the Supreme Court’s decision in Association of Molecular Pathology v. Myriad Genetics, Inc., and will be further narrowed in the next few years as many of its still-valid patents expire. But these developments have not caused the company to acquiesce in competition. Instead, it has launched a litigation offensive against a number of actual and potential competitors, suing them for infringement of numerous unexpired patents that survived the Supreme Court case.

A parallel strategy may have even greater long-term significance, however. In announcing expanded operations in Europe, Myriad has emphasized that it will rely less on patents and more on its huge proprietary database of genetic mutations and associated health outcomes—a strategy that could be used in the United States as well. Myriad has built that database over its many years as a patent-based monopolist in the BRCA testing field, and has not shared it with the medical community for more than a decade. Consequently, Myriad has a unique ability to interpret the health significance of patients’ genetic mutations, particularly in the case of rare “variants of unknown significance.”

This Article reviews the current state of Myriad’s patent portfolio, describes its ongoing litigation offensive, and then analyzes its proprietary database strategy. The Article argues that Myriad’s strategy, while legally feasible, undercuts important values and objectives in medical research and health policy. The Article identifies several ways in which the research and health care communities might fight back, but acknowledges that it will be a difficult uphill fight.

]]>http://www.genomicslawreport.com/index.php/2014/08/04/new-article-on-myriad-litigation-and-the-companys-evolving-strategy/feed/0Long-Awaited Announcement from the FDA on LDTshttp://www.genomicslawreport.com/index.php/2014/08/01/long-awaited-announcement-from-the-fda-on-ldts/
http://www.genomicslawreport.com/index.php/2014/08/01/long-awaited-announcement-from-the-fda-on-ldts/#commentsFri, 01 Aug 2014 16:27:47 +0000http://www.genomicslawreport.com/?p=13333On July 31, 2014, the FDA gave Congress notice that in the next 60 days it would be announcing draft guidelines on the regulation of laboratory developed tests (LDTs). This topic has been discussed on the Genomics Law Report frequently for years. [You can access the previous coverage here].

The FDA’s notice to Congress does indicate that at least some LDTs are not going to be caught up in the FDA’s forthcoming LDT framework, including those used solely for law enforcement purposes and certain LDTs used for transplantation. Not surprisingly, the FDA indicates it will apply its risk-based classification of medical devices to evaluate LDTs. Does this notice signal that the ultimate regulatory regime is finally in sight? Well, some of the provisions even in this draft guidance (not finalized guidance) would take almost a decade to implement. The FDA suggested it wouldn’t have descriptions of what it generally considers to be Class I, II, and III (the risk-based medical device categories) LDTs for 18 months after the guidance is finalized. Likewise, enforcement of the premarket review requirements for Class II LDTs is scheduled to be phased in gradually (>5 years after the finalized guidance) and only after the FDA has completed implementing the requirements for Class III LDT premarket reviews (which it estimates would take ~4 years after finalized guidance).

It will be necessary to be patient once more, await the Federal Register notice of the Draft Guidance in a few weeks, and then consider the actual requirements proposed. However, it is interesting at this stage to highlight one point of the FDA’s notice to Congress. The FDA buried this gem in footnote 4:

“FDA generally does not exercise enforcement discretion for direct-to-consumer (DTC) tests regardless of whether they meet the definition of an LDT provided in this guidance. Therefore, the enforcement policies in this guidance do not apply to DTC tests, and the FDA’s usual enforcement policies apply to DTC tests.”

Huh? The FDA does not generally exercise enforcement discretion for DTC genetic tests? To “exercise enforcement discretion,” in FDA jargon, is to choose not to regulate something that the agency might have the authority to regulate. So the FDA is saying here—hold on for a jarring double negative—that it does not choose not to regulate DTC tests, and that, consequently, DTC tests fall under “usual enforcement policies”? The FDA asserting authority over DTC tests and reconsidering its enforcement discretion is one thing, but rewriting the regulatory history is quite another.

There are countless reasons why this footnote is historically inaccurate. If this were true, why would so many publications call for FDA oversight of DTC tests? And, in response to all those scholarly publications, why would the FDA not have issued a simple corrective comment on its website saying, “Hey idiots, these are regulated. Here’s how”? If DTC genetic tests were regulated under “usual enforcement policies” all this time, why would the topic be listed by the FDA on its B-List for draft guidance in FY2014? Why would legal scholars debate the shift in language from the 2010 letters to the 2013 letters on whether DTC genetic tests are “medical devices”? Why would other scholars complain that we’ve been anxiously tapping our feet awaiting rules on the regulation of DTC genetic tests that were thought to have been ready in 2012? Why would the National Human Genome Research Institute website indicate, “The Food and Drug Administration (FDA) has the authority to regulate genetic tests, but it has to date only regulated the relatively small number of genetic tests sold to laboratories as kits.” Why would SACGHS, in direct contradiction to the FDA’s latest statement, report in 2010 that the “…FDA generally exercises enforcement discretion for most LDTs, including DTC genetic tests developed as LDTs?”

Let’s reserve judgment until the actual draft guidance is published in the Federal Register. Until then, we can all learn at least one important lesson from the FDA’s announcement: always read the footnotes.

]]>http://www.genomicslawreport.com/index.php/2014/08/01/long-awaited-announcement-from-the-fda-on-ldts/feed/0FTC Takes Action to Protect Consumers from False Genetic Advertising Claimshttp://www.genomicslawreport.com/index.php/2014/07/03/ftc-takes-action-to-protect-consumers-from-false-genetic-advertising-claims/
http://www.genomicslawreport.com/index.php/2014/07/03/ftc-takes-action-to-protect-consumers-from-false-genetic-advertising-claims/#commentsThu, 03 Jul 2014 13:00:44 +0000http://www.genomicslawreport.com/?p=13323For the past few years, discussions regarding the regulatory oversight of direct-to-consumer (DTC) genetic tests have focused heavily on one agency: the FDA. Attention has grown since 2010 when the FDA began hinting the agency would broadly regulate laboratory developed tests (LDTs) and has only intensified since the issuance of the infamous cease-and-desist letter issued to 23andMe in late 2013. Now 23andMe and the FDA are hitting the reset button to begin the long road to restore 23andMe’s Personal Genome Service® one condition or trait at a time (the company announced on June 20, 2014 that it has filed, and the FDA has accepted for review, its first 510(k) application for Bloom Syndrome). The personal genomics industry continues to wait anxiously for the FDA proposed rules on DTC genetic tests, which are on the FDA’s Draft Guidance “B-List” for FY2014 (i.e., DTC genetic tests are not among the FDA’s top priorities).

Perhaps it’s time another administrative agency is brought into the discussion. This year the Federal Trade Commission (FTC) has taken its first actions to protect consumers of genetic tests. The FTC has broad authority to protect consumers from unfair and deceptive trade practices (including false and misleading advertising claims) under Section 5(a) of the FTC Act, 15 U.S.C. 45(a)(1). The FTC also enforces posted corporate privacy policies. The FTC filed charges against two companies in January (Genelink, Inc. and its former subsidiary foru™ International Corporation) and filed charges against a third company in June (L’Oreal USA, Inc.) for “purported personalized genomics products.” The charges related to the marketing of nutrigenetic and dermagenetic products. The matters against the first two companies were resolved by settlement approved on May 12, 2014. The FTC announced a proposed settlement of the charges against L’Oreal on June 30, 2014.

A Brief Overview of How the FTC Works
The FTC has investigative and enforcement authority to protect consumers under the FTC Act. When the FTC has reason to believe that the FTC Act has been violated, it may initiate charges against a party. The party (called the “respondent”) may elect to settle the charges by entering into a consent agreement or consenting to a final order and waiver of judicial review or, alternatively, may contest the charges. When the charges are settled rather than challenged by the respondent, a proposed settlement agreement is put into a “decision and order” that is open for public comment for at least 30 days. After the public comment period has expired, the order is made final (sometimes with modification in response to the public comments) and becomes binding 60 days after it is served. The orders may include injunctive relief, including bans on the respondent engaging in certain practices. If the respondent contests the charges, an administrative law judge presides over a trial and makes an “initial decision.” A respondent may appeal the initial decision to the full Commission, which then issues a “final decision.” Final decisions may be appealed to the U.S. Court of Appeals and, ultimately, to the Supreme Court.

Advertising Genetic-Related Benefits
The Genelink and foru™ products at issue were LifeMap ME DNA Customized Supplements, GeneWize Nutritional Supplements, LifeMap ME DNA Customized Skin Repair Serum, and GeneWize Customized Skin Repair Serum. Genelink and foru™ had made claims that their nutritional products customized to the customer’s genotypes could “compensate for an individual’s genetic disadvantages” and act as “SNP boosts.” L’Oreal products at issue were Lancôme Génifique and L’Oréal Paris Youth Code skincare products. L’Oreal made claims that their cosmetics would “boost the activity of genes” for skin regeneration. The FTC complaint alleged the advertising claims and business practices of the three companies constituted “unfair or deceptive trade practices” and, therefore, were in violation of Section 5(a) of the FTC Act, 15 U.S.C. 45(a)(1).

Compliance with Posted Privacy Policies
In addition to the advertising problems, the FTC charged that Genelink and foru™ also engaged in unfair and deceptive trade practices regarding the execution of the companies’ posted privacy policies, by having failed to maintain adequate and reasonable data security for its customers’ personal information (including, e.g., genetic and financial information). Thus, the FTC charged the companies with violations of both Section 5(a) and Section 12 of the FTC Act, which specifically prohibits false ads likely to induce the purchase of food, drugs, devices, or cosmetics.

Burdens of Scientific Proof to Substantiate Claims of Genetic-Related Benefits
In the matters involving Genelink and foruTM, the FTC commissioners were split (3-1), with Commissioner Ohlhausen specifically dissenting from the decision and order on the basis that it set an “unduly high standard…to substantiate any disease-related claim” and that that unduly high standard “may, in many instances, prevent useful information from reaching consumers in the marketplace and ultimately make consumers worse off.” The decision and order prohibited the companies from claiming its products “will treat, prevent, mitigate, or reduce the risk of any disease – by modulating the effect of genes, or based on a consumer’s customized genetic assessment – unless the claim is true and supported by at least two adequate and well-controlled studies.” The order defined an adequate and well-controlled study as:

“a human clinical study that: is randomized and adequately controlled; utilizes valid end points generally recognized by experts in the relevant disease field; yields statistically significant between-group results; and is conducted by persons qualified by training and experience to conduct such a study. Such study shall be double-blind and placebo-controlled…”

The order specified that if the companies claim a product is effective for persons with a particular genetic variation or SNP (i.e., a single nucleotide polymorphism), then the studies “shall be conducted on human subjects with such genetic variation or SNP.”

The FTC considered and rejected concerns raised by the Council for Responsible Nutrition that its proposed orders against Genelink and foru™ created a de facto two random clinical trial standard on any health-related advertising claims made by the food and diet industry and by the Natural Products Association that setting such an industry standard requires the issuance of formal guidance.

The FTC Chairwoman Edith Ramirez and Commissioner Julie Brill explained, “In this and other recent enforcement actions, the Commission has consistently adhered to its longstanding view that the proper level of substantiation for establishing liability is a case-specific factual determination as to what constitutes competent and reliable scientific evidence for the advertising claims at issue.” They further explained that the two randomized clinical trials per claim was not necessary for assessing liability against Genelink and foru™ but, rather, was included in the injunctive order as an appropriate “fencing-in” provision to prevent the two companies from repeating the alleged unlawful conduct.

Commissioner Wright stated that the FTC “inevitably faces a tradeoff between deterring deceptive advertising and preserving the benefits to competition and consumers” and encouraged the FTC to “explore more fully whether the articulation and scope of injunctive relief in these and similar settlements strikes the right balance.” According to Commissioner Wright, “[t]he optimal amount and type of evidence to substantiate a future claim will vary from case to case.”

In the more recent decision and order with L’Oreal, the FTC defined “Competent and reliable scientific evidence” as “evidence, consisting of tests, analyses, research, or studies that have been conducted and evaluated in an objective manner by qualified persons and are generally accepted in the profession to yield accurate and reliable results.” Unlike the earlier order against Genelink and foru™, the FTC did not mandate that L’Oreal have at least two random clinical trials to substantiate each of its claims. L’Oreal is simply enjoined from advertising that its skincare products affect genes until it has “competent and reliable scientific evidence.” The “fencing in” provision of the L’Oreal order extends this requirement to any gene-related claims for all L’Oreal’s cosmetics, not just its skincare. The decision and order will be open for public comment for 30 days.

What does this mean for other companies?
The FTC seems content to protect consumers from false or misleading advertising by determining, on a case-by-case basis, what level of scientific proof is necessary to substantiate each gene-related claim. In January, FTC Chairwoman Ramirez and Commissioner Brill explained in their separate statement, “…to the extent other marketers look to our orders for signals as to the type of backing required for disease treatment claims, we prefer that they understand that serious claims like those made by respondents [Genelink and foru™] must have hard science behind them.” Additionally they made clear that when claims are made in reliance upon emerging science the claims should be qualified accordingly. “Properly qualified claims are lawful and permissible.” Companies offering nutrigenetic and dermagenetic products have three options to stay out of trouble with the FTC: avoid referencing gene-related benefits altogether, insert (at a minimum) caveats to any gene-related claims, or (ideally) provide substantial scientific evidence to support any gene-related claims made.

]]>http://www.genomicslawreport.com/index.php/2014/07/03/ftc-takes-action-to-protect-consumers-from-false-genetic-advertising-claims/feed/0Property Rights and the Human Bodyhttp://www.genomicslawreport.com/index.php/2014/06/11/property-rights-and-the-human-body/
http://www.genomicslawreport.com/index.php/2014/06/11/property-rights-and-the-human-body/#commentsWed, 11 Jun 2014 13:50:56 +0000http://www.genomicslawreport.com/?p=13297A Canadian court made headlines this month when it decided, as a preliminary matter, that human tissue removed from the body for diagnostic medical tests is “personal property” that belongs to the hospital where the procedure was performed. The case was a medical negligence action brought against two doctors by the estate of Snezana Piljak, a woman who was diagnosed in 2009 with colorectal cancer and died in 2011. At issue in the case is whether the doctors were negligent in failing to diagnose the cancer in 2008 when a colonoscopy was performed on Ms. Piljak. The doctors had petitioned the Canadian court for access to liver tissue biopsied from Ms. Piljak in 2009 at Toronto’s Stonybrook Hospital. The court had to address the matter of tissue ownership before it could consider whether the defendant-doctors had a right to access the liver tissue in order to investigate whether Ms. Piljak had hereditary non-polyposis colorectal cancer (HNPCC or Lynch Syndrome). If the HNPCC were indicated by an examination of the tissue, the defendant-doctors would use that fact to mount a defense against the accusations of negligence. The court ruled that the tissue was personal property of the hospital (though it ultimately denied the defendant-doctors’ request to examine it for technical reasons). The decision that human tissue is “personal property” has important legal ramifications that might affect the biotech industry and genetic research community outside of Canada. The question of ownership of biospecimens has often been tangled up with the status of the biospecimens as personal property, though they are distinct questions.

The case generally cited in the United States on this issue of whether there are property rights in human tissues is Moore v. Regents of the University of California, 793 P.2d 479 (Cal. 1990). There, the California Supreme Court denied John Moore’s conversion claim (conversion is, in basic terms, civil theft), rejecting the argument that an individual has property interests in his cells or other unique products of the body and ruling that the individual could not share in commercial profits generated from research performed on the individual’s biospecimens. As we explained previously while highlighting various state legislative efforts to establish genetic rights by defining DNA or genetic information as “personal property” or “real property,” the underlying rationale for the Moore decision was that a legal recognition of property rights in biospecimens would have a chilling effect on medical and scientific research. A more recent case in this area of property interests in biospecimens is Washington University v. Catalona, 409 F.3d 667 (8th Cir. 2007), in which the Eighth Circuit Court of Appeals decided that individuals who provided biospecimens (such as blood or tissue) for genetic cancer research did so as inter vivos gifts (i.e., gifts made during one’s life, as opposed to testamentary gifts made after death) and, accordingly, retained no property rights that would allow them to request the return of the biospecimens or the transfer of the biospecimens to a third party. The rationale in Catalona was that the research participants voluntarily donated the samples for the research: once a donative transfer was complete (i.e., once the donor delivers and the donee accepts the gift, here biospecimens), the gift cannot be revoked.

Just last year special rules were developed for genomic research involving HeLa cells, allowing the heirs of Henrietta Lacks to exert some influence over genomic research involving cell lines derived from Ms. Lacks’ cervical tumor tissues that had been collected in 1951. Difficult questions (such as who owns our biospecimens, who owns our genome, and who owns commercial products derived from our biomedical research contributions) swirled after Rebecca Skloot brought the story of Henrietta Lacks and the origin of HeLa cells to the public’s attention in 2010. While the new rules do not involve compensation or rights to benefit from products or discoveries made with HeLa cells, the new rules did create a HeLa Genome Data Access Working Group, upon which the family members of Henrietta Lacks will have representation, that will assist in a case-by-case determination about whether access to HeLa genomic data should be granted. The new rules also mandate that any publication of HeLa sequence data be deposited in dbGaP, a controlled-access database, and request that any publications acknowledge the generous contributions Henrietta Lacks and her family have made to science. Advances in biomedical science, bioengineering, and consumer/participatory science are prompting property questions to resurface (such as the implications of bankruptcy by direct-to-consumer companies and DNA databases as valuable corporate assets).

When we assign a property label to something (such as human tissue or a DNA sample), we assign corresponding rights and obligations, and this legal classification ultimately shapes societal conduct. Property law principles promote and facilitate transfers or, contrastingly, deter and restrict transfers. Statutes of fraud require that agreements to sell real property be in writing whereas personal property can be transferred by verbal agreement. How the law currently treats and has historically treated the human body (in whole and in part) in various contexts (e.g., medicine, research, education, employment, immigration, etc.) reflects the political desire to encourage or discourage certain conduct.

It should go without saying that people (i.e., living human bodies) cannot lawfully be another person’s chattel (U.S. Const. 13th Amend.). Does this necessarily mean that one cannot have recognizable property rights in one’s own body and must rely solely on privacy rights for protection of bodily integrity? I don’t think so.

Still, the commodification of the human body poses challenging legal questions. For example, the market for human breast milk has policymakers wondering what oversight is needed to promote infant nutrition and safety of breast milk consumption. (The FDA does not regulate the sale of breast milk but discourages online and person-to-person sharing. Breast milk, the FDA, and food safety laws are a bit tangential to the present discussion.) Our struggles to define genetic property rights have highlighted inconsistencies in US policy, particularly when it comes to deciding whether compensation is appropriate and permissible, or a coercive force, and thus impermissible. For example, organ donation is encouraged, but policies prevent the use of financial incentives to increase the number of organ donors and to make organ donation less disruptive to the life of the donor. While the Uniform Anatomical Gift Act does not mention the sale of organs, the word “gift” has been interpreted to mean that transfers must be donative (i.e., without compensation). The National Organ Transplant Act’s ban on the sale of organs does not apply to all bodily products (e.g., blood, sperm, or ova) and does not prohibit all forms of compensation (e.g., NOTA allows reasonable compensation for the organ procurement procedures but prohibits compensation for the bodily source product). Considerable controversy continues over whether bone marrow should be treated more like an organ or blood and, accordingly, whether bone marrow donors can be compensated. Distinctions on the compensation issue have been made on whether the bodily product “can be replenished” and whether the donation “does not compromise the health of the donor.” Oocyte (egg) donors are permitted by guidelines established by the American Society for Reproductive Medicine and Society for Assisted Reproductive Technology to receive $5,000-10,000 but receipt of anything more is considered coercive. Who has the right to set the price on a woman’s eggs: the individual producer, the market, the industry, or the regulators? Iran is currently the only country to allow living kidney donors to be paid, and recent data contrasting related donors and unrelated paid donors have been reported. Plenty of arguments suggest that permitting the sale of organs would in essence mean that organs would go to the highest bidder and that this, in turn, would not only incentivize the poor to become donors but also prevent them from being recipients (See, e.g., Walter Mosley’s short story “Whispers in the Dark” in Futureland). It’s yet unclear what reforms to property, anatomical gifts, and organ donor laws will be prompted by bioprinting of organs and body parts (e.g., successful transplants of 3D printed pelvises, vertebrae, and jaws have been performed) and growing organs and body parts (like vaginas and noses) in labs.

Recognition of personal property rights in human bodies (in whole or in part) makes many legal scholars, bioethicists, and biotech industry people (among others) uncomfortable. But should that necessarily be the case? There are many aspects of property law principles that are intriguing when considered in the context of biomedical research. Would recognition of personal property rights in one’s own biospecimens make it conceptually less challenging for an individual to make contributions to research or medicine – either by donating, selling, or even licensing materials to researchers? Would it help researchers better manage risks by allowing them to set liquidated damages or pay premiums for permission to use biospecimens for particular purposes? Other principles might be less desirable. For example, if property interests were recognized in tissues, could tissues be taken by government agencies (e.g. the NIH or NSF) as government condemnation through powers of eminent domain? How would public and private necessities apply to biospecimens, potentially enabling emergency or limited uses of the property without the owner’s prior consent? Would recognition of property rights allow us to apply concepts of concurrent ownership (e.g., joint owners) or future interests to genetic information in certain contexts? (e.g., having joint EMRs that allow BRCA1/2 risk information to be visible across records for sisters or records of mothers and daughters)? Would the promotion of such transfers through recognition of novel or existing property principles serve as an equalizer and mediate the harms of body part and human trafficking for medical and research purposes or, conversely, would it further disenfranchise, marginalize, and exploit those same populations whose members suffered (and continue to suffer) from slavery and the treatment of human beings as chattel?

A recognition that human tissues are “personal property” is entirely separate from the question of who owns the property. Facts similar to those in the Canadian case involving the Estate of Ms. Piljak may very well lead U.S. courts to reach similar conclusions and continue to follow Moore precedent. It may cause us to revisit fundamental questions in biomedical research settings (e.g., what is medical waste and what are the meaningful differences between an informed consent document and a contract). Yet this acknowledgement as a preliminary matter that the biospecimens are personal property does provide us flexibility to move forward and focus on important questions regarding the corresponding rights and obligations that that classification entails (e.g., possession, title, and ability to transfer) and discuss pressing policy issues (such as whether limitations should be imposed as act, actor, subject, or purpose constraints). I welcome a renewed property discussion in the area of biomedical research. A property designation on biospecimens need not imply that donors have legal interests that survive the completed transfer of biospecimens and entitle them to claim a share in IP-based profits down the road. Moreover, a bill of sale to transfer rights in specific biospecimens would be refreshingly clear and final (and of interest to only a subset of the human population willing to take the risks associated with such a transaction) and could be permitted without undermining human research participant protections. It is vital, however, that in addressing whether and how we might apply property principles to biospecimens, we stay committed to human rights and, accordingly, remain focused on ensuring the equality and dignity of all human beings.

Acknowledgement: Thanks to Misha Angrist for helpful feedback on an early draft of this post.

]]>http://www.genomicslawreport.com/index.php/2014/06/11/property-rights-and-the-human-body/feed/0Biometrics: A Developing Regulatory Landscape for a New Era of Technologyhttp://www.genomicslawreport.com/index.php/2014/05/21/biometrics-a-developing-regulatory-landscape-for-a-new-era-of-technology/
http://www.genomicslawreport.com/index.php/2014/05/21/biometrics-a-developing-regulatory-landscape-for-a-new-era-of-technology/#commentsWed, 21 May 2014 14:34:14 +0000http://www.genomicslawreport.com/?p=13288James Bond and Ethan Hunt have been using facial recognition, fingerprint scanning, and optical readers for years on the silver screen. In the real world, the use of technology that identifies unique physical characteristics of individuals (“biometrics”) is rapidly becoming more prevalent. In fact, the Department of Homeland Security uses facial scanning to identify potential terrorists, federal agencies have adopted fingerprint technology to confirm the identity and immigration status of aliens, and private entities have begun implementing palm and retina scanners and other identifiers to complete financial transactions or control access to secure information. Even the new iPhone 5 contains “Touch ID” technology, where a sensor quickly reads the user’s fingerprint and automatically unlocks the phone for the correct fingerprint.

There are two general types of biometric data: physiological and behavioral. Physiological data includes facial structure, retinal color and design, fingerprint readings, heat signatures, and DNA readings. Behavioral data includes handwriting samples and signatures, voice recognition, and keyboard stroke and typing habits. Physiological and behavioral data are generally used for either authentication (e.g., accessing a computer with a retinal scan) or identification (e.g., determining who used the computer by analyzing keystrokes). Although these technologies advance security and create new efficiencies, they also raise privacy concerns. Some biometric collection methods can be invasive or inaccurate, leading to false identification of an individual that could have serious repercussions, such as the misidentification of a citizen as an illegal alien. They may also result in multiple entities storing massive amounts of sensitive personal information.

As with other technology, biometrics is moving faster than the pens of most law makers. While federal and state search and seizure law (as well as several specific state laws, discussed below) governs any collection and use of biometric data by a governmental entity, no current federal law limits a private entity’s ability to collect, use, or disclose biometric data. Instead, the regulation of the private use of biometric data has largely been left to the states.

Although biometrics is still in its infancy from a regulatory perspective, several states have enacted statutes directly addressing the topic. Both Illinois (the Illinois Biometric Information Privacy Act, 740 ILCS 14/1, et seq.) and Texas (Bus. & Com. Code Ann. § 503.001) regulate a private entity’s use, disclosure, and eventual destruction of biometric data. Illinois obligates private entities that collect biometric data to develop written policies describing their biometric data collection methods. Both Illinois and Texas restrict the sale or lease of, or profit from, biometric data except in limited circumstances. The cost of noncompliance can be high. Under the Illinois law, violators may be subject to a private suit filed by an individual whose biometric data has been compromised. Damages for each violation are the greater of liquidated damages ($1,000 for a negligent violation or $5,000 for an intentional or reckless violation) or actual damages, and injunctive relief and attorneys’ fees and costs are also available. Texas subjects violators to a civil penalty (which may be enforced by the Texas Attorney General) of up to $25,000 for each violation. In addition to the comprehensive Illinois and Texas laws, several states (Iowa, Nebraska, North Carolina and Wisconsin) include various types of biometric data in their definition of “personal information” for purposes of data security breach notification laws, which require notice to data owners in the event of a data breach involving such information. Finally, New York prohibits private employers from fingerprinting their employees as a condition of securing or maintaining employment except in limited circumstances.

Several states have enacted laws governing the collection, use or disposal of biometric information by state entities, but the substance of these laws varies widely from state to state. Washington and Oregon have authorized their respective drivers’ licensing departments to use facial recognition technology to prevent individuals from obtaining multiple or fraudulent licenses. Only the Washington law restricts the licensing department’s ability to share or disclose the biometric data it collects. Maine, Missouri and New Hampshire, on the other hand, expressly prohibit the use or collection of biometric data in connection with drivers’ licenses. Arizona, Illinois and Louisiana prohibit schools from collecting biometric data from students before first obtaining parental consent and place restrictions on the use, storage, and destruction of such information. Texas broadly prohibits the governmental bodies from selling, leasing, or disclosing an individual’s of biometric data without first obtaining that individual’s consent, except in connection with disclosures required by law or in connection with law enforcement.

Even if a specific state law does not apply, private entities that collect biometric data from their employees may face class action claims based upon federal or state laws prohibiting discrimination. For example, in 2013 the Equal Employment Opportunity Commission sued an employer in West Virginia alleging religious discrimination in violation of Title VII of the Civil Rights Act of 1964 in connection with the use of biometric technology for tracking employee time and attendance. An evangelical Christian employee believed that submitting to a workplace hand scanner had a connection to the “Mark of the Beast” as referenced in the Bible’s Book of Revelation. The employee asked the company to accommodate his religious beliefs by allowing him to track his time by reporting to his supervisor or submitting manual time records, but the company refused, and the employee filed an EEOC charge that ultimately resulted in the lawsuit. As of the date of this article, the lawsuit is still in the discovery stage, with trial set for late 2014.

As biometric technology becomes more common in mobile devices and in the workplace, more states are likely to enact comprehensive biometric privacy laws like those in Illinois and Texas. While the biometrics landscape continues to develop on a state and federal level and many of the existing laws remain largely untested, private entities should carefully review their policies and procedures now to determine if they collect or use biometric information, and if so, engage a qualified attorney to determine what their rights, obligations, and potential liabilities are as to such practices.

]]>http://www.genomicslawreport.com/index.php/2014/05/21/biometrics-a-developing-regulatory-landscape-for-a-new-era-of-technology/feed/0ACMG Backs Down a Bithttp://www.genomicslawreport.com/index.php/2014/04/07/acmg-backs-down-a-bit/
http://www.genomicslawreport.com/index.php/2014/04/07/acmg-backs-down-a-bit/#commentsMon, 07 Apr 2014 13:00:47 +0000http://www.genomicslawreport.com/?p=13272A year ago, the American College of Medical Genetics and Genomics (ACMG) released its Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. As I reported in a July 2013 post, the core recommendation was this: “The ACMG recommends that for any evaluation of clinical sequencing results, all of the genes and types of variants in the Table should be examined and the results reported to the ordering physician.” Specifically, the ACMG recommended that whenever a lab does whole genome or whole exome sequencing on a patient, it should examine all 57 [now 56] genes on the list included in the Recommendations and report any clinically significant findings to the ordering physician. It would then be the duty of that physician “to provide comprehensive pre- and post-test counseling to the patient.” Most controversially, the ACMG recommended that the test findings “be reported without seeking preferences from the patient and family and without limitation due to the patient’s age.” As I characterized it in the July post, “patients should be given the 57-gene screening whether they want it or not and told the results even if they say they don’t want them.”

A huge controversy erupted. Critics stressed the apparent affront to the ethical principle of patient autonomy, the limited state of medical knowledge about the pathway from genetic mutations to disease, the problems in deciding what conditions are “amenable to medical intervention,” and the special concerns presented by applying the Recommendations to child patients (note “without limitation due to the patient’s age,” above). (There was inconsistency in the ACMG’s application of the Recommendations to children. As GLR Contributing Editor Jen Wagner has written elsewhere, before it issued the Recommendations the ACMG had issued a joint policy statement with the American Academy of Pediatrics that stressed the need for parental involvement in the genetic testing of newborns and children.)

As the controversy over the Recommendations unfolded, journals published special issues devoted to the topic. The ACMG published a “Clarification” in the journal it sponsors, Genetics in Medicine, that dealt with the major issues raised by the critics, but it did not modify the Recommendations. Now the ACMG is backing down, at least a bit, and showing greater deference to patient autonomy. In an April 1, 2014, press release, the ACMG announced that its board of directors had voted to approve an “update” to the recommendations. The revised version recommends that patients be offered “an opportunity to opt out of the analysis of medically actionable genes when undergoing whole exome or genome sequencing.” The opt out discussion between doctor and patient should take place at “the point where the sample is sent [to the lab] rather than at the time when results are received by the clinician, as was originally recommended.” The update is said to have followed the expression of “divergent and valuable opinions” by the ACMG membership, and to reflect an apparent “consensus among ACMG members.”

As I understand the updated approach, the right to opt out would involve the analysis and interpretation of the sequencing results. The sequencing of the whole genome or exome would be done in any event. If a patient opted out of part of the 56-gene panel, the patient’s sequence at the relevant loci would not be analyzed, meaning that there would be no interpretive findings for the lab to return to the clinician and patient. The opt-out right would not put the lab and doctor in the position of having findings that they would then have to keep from the patient—that information would not be generated in the first place.

My UNC colleague Jim Evans, a medical geneticist who is a leading participant in genomic policy debates, had recommended just such a change—he called it a “compromise”—last fall. In an October 2013 editorial accompanying a special issue of Genetics in Medicine, which he edits (and where the ACMG will publish the current and any future updates), Evans wrote: “let us routinely examine the ‘ACMG 56’ for clearly deleterious mutations when genome-scale sequencing is performed. But let us allow patients to opt out of such analysis of their specimen.” He went on to stress that he was “uncomfortable” with his recommendation, because it “affords patients an illusory degree of autonomy and that, in reality, discussions about an unlikely and hypothetical scenario that they choose to opt out of that does not really boil down to an informed choice.” I think the point is that it would be difficult for a patient to grasp what it is like to be in the unlikely situation of receiving a positive report about a potentially dangerous mutation; hence, any choice based on an evaluation of such a situation would be ill-informed. Nonetheless, Jim concluded, this compromise, with discomfort on both sides, represents the best currently-available approach.

I agree with everything Jim Evans said, and thus with the ACMG’s new approach. I sympathize with doctors who are concerned about having to practice with one metaphorical hand tied, unable to obtain and use potentially significant information about their patients. But I think that patient autonomy—even if “illusory”—is the higher value in this case. This is particularly true because of the relatively attenuated clinical value of at least some of the information that is at stake here: patient choices may be ill-informed, as Jim said, but nobody is fully informed, as critics of the original ACMG Recommendations argued. Patients should not have autonomy to make doctors do things that contradict their best medical judgment, but they should be able to make them refrain from doing things.

A final question is the one I raised in my original post: what is the practical effect of the Recommendations, as originally promulgated and now as updated? Do they now constitute a mandate to physicians and a standard of care for genetic medicine?